EP3265461B1 - Verbascosid-derivate - Google Patents
Verbascosid-derivate Download PDFInfo
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- EP3265461B1 EP3265461B1 EP16712512.9A EP16712512A EP3265461B1 EP 3265461 B1 EP3265461 B1 EP 3265461B1 EP 16712512 A EP16712512 A EP 16712512A EP 3265461 B1 EP3265461 B1 EP 3265461B1
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- European Patent Office
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- verbascoside
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- KDSWDGKIENPKLB-QJDQKFITSA-N verbascoside Chemical class O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](OC(=O)CCC=2C=C(O)C(O)=CC=2)[C@@H](CO)O[C@@H](OCCC=2C=C(O)C(O)=CC=2)[C@@H]1O KDSWDGKIENPKLB-QJDQKFITSA-N 0.000 title description 34
- 150000001875 compounds Chemical class 0.000 claims description 41
- 238000011282 treatment Methods 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 239000003146 anticoagulant agent Substances 0.000 claims description 12
- 230000002744 anti-aggregatory effect Effects 0.000 claims description 10
- 206010012601 diabetes mellitus Diseases 0.000 claims description 9
- 125000004185 ester group Chemical group 0.000 claims description 7
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- QFRYQWYZSQDFOS-UHFFFAOYSA-N verbascoside Natural products CC1OC(COC2C(O)C(COC3OC(C(O)C(O)C3O)C(=O)O)OC(Oc4cc(O)cc5OC(=CC(=O)c45)c6ccc(O)c(O)c6)C2O)C(O)C(O)C1O QFRYQWYZSQDFOS-UHFFFAOYSA-N 0.000 description 31
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 21
- 239000000243 solution Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 8
- HHEAADYXPMHMCT-UHFFFAOYSA-N dpph Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1[N]N(C=1C=CC=CC=1)C1=CC=CC=C1 HHEAADYXPMHMCT-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 230000003111 delayed effect Effects 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 229960001138 acetylsalicylic acid Drugs 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 5
- 239000000902 placebo Substances 0.000 description 5
- 229940068196 placebo Drugs 0.000 description 5
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 4
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 4
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- 238000004220 aggregation Methods 0.000 description 4
- 229940114079 arachidonic acid Drugs 0.000 description 4
- 235000021342 arachidonic acid Nutrition 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 230000009862 primary prevention Effects 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 244000297179 Syringa vulgaris Species 0.000 description 3
- 235000004338 Syringa vulgaris Nutrition 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 238000011458 pharmacological treatment Methods 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 125000005546 pivalic acid group Chemical group 0.000 description 2
- 210000004623 platelet-rich plasma Anatomy 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 1
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 1
- 239000005465 B01AC22 - Prasugrel Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 206010039020 Rhabdomyolysis Diseases 0.000 description 1
- 241000364021 Tulsa Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000002225 anti-radical effect Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
- 229960003009 clopidogrel Drugs 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 208000001780 epistaxis Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 238000013167 light transmission aggregometry Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical compound C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 description 1
- 229960004197 prasugrel Drugs 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- -1 radical 2,2-diphenyl-1-picrylhydrazyl Chemical class 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 1
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 description 1
- 229960002528 ticagrelor Drugs 0.000 description 1
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
- 229960005001 ticlopidine Drugs 0.000 description 1
- 230000006441 vascular event Effects 0.000 description 1
- 230000006439 vascular pathology Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Definitions
- Cardiovascular diseases are a chronic pathology which develops insidiously during an individual's life and often it is symptomatic only when it has already reached an advanced stage. This pathology is still the leading cause of premature death in Western countries and in any case, due to its extensive dissemination, it often leads to mass disability because of its characteristic incapacitating symptomatology.
- statins are the most effective hypolipidemic drugs for the primary prevention of cardiovascular diseases and are generally well tolerated. Nevertheless, some patients show side effects such as high hepatic enzyme levels, gastrointestinal symptoms and myalgia, myositis and statin-induced rhabdomyolysis. In these patients, alternative therapies with natural substances have been proposed to keep hypercholesterolemia under control.
- aspirin is not effective in the treatment of diabetic patients due to its mechanism of action.
- Verbascoside is a polyphenol of formula: which may be extracted from plants or cell lines, such as Syringa vulgaris, and which has anti-oxidizing, cicatrizing, and cardio-protective activity.
- verbascoside also has platelet antiaggregant activity via the modulation of two mechanisms, i.e. one involving arachidonic acid, cyclooxygenase and thromboxane A2, and a second one acting through ADP and P2Y12 receptor.
- verbascoside can also be used as a platelet antiaggregant in the treatment of diabetic patients, who vice versa would not be responsive to a therapy with acetylsalicylic acid.
- said pharmacological activity is present in verbascoside derivatives of formula (I) where R, R 1 , R 2 and R 3 are equal or different and are independently selected from hydrogen and carboxylic acid residue, so that the ester groups R-O-, R 1 -O-, R 2 -O- and R 3 -O-, respectively, can be hydrolyzed at a pH from 4.5 to 7, provided that R, R 1 , R 2 and R 3 are not simultaneously hydrogen; and wherein at least one of R, R 1 , R 2 and R 3 is a residue of pivalic acid.
- said derivatives may give rise to the formation of verbascoside in vivo, e.g. via the action of hepatic enzymes or, partially, in blood, with delayed-release kinetics. Nevertheless, with respect to verbascoside, said compounds have greater oxidation stability, such as that occurring in a normal aqueous saline solution, which allows a pharmaceutical formulation to be prepared in the form of a solution which remains stable over time.
- a compound of formula (I) as defined above for use as a platelet antiaggregant, is a first object of the present invention.
- the compounds of formula (I) as defined above, for use as platelet antiaggregants in the treatment of diabetic patients, in particular of diabetic patients at risk for cardiovascular diseases, are an additional object of the invention.
- This invention relates to compounds of formula (I): where R, R 1 , R 2 and R 3 are equal or different and are independently selected from hydrogen and a carboxylic acid residue, so that the ester groups R-O-, R 1 -O-, R 2 -O- and R 3 -O-, respectively, can be hydrolyzed at a pH from 4.5 to 7, provided that R, R 1 , R 2 and R 3 are not simultaneously hydrogen; and wherein at least one of R, R 1 , R 2 and R 3 is a residue of pivalic acid. for use as a platelet antiaggregant.
- ester groups R-O-, R 1 -O-, R 2 -O- and R 3 -O-, respectively, are hydrolyzed at a pH from 5 to 6.5.
- ester groups R-O-, R 1 -O-, R 2 -O- and R 3 -O-, respectively, are hydrolyzed at a pH from 6 to 7, preferably from 6.3 to 6.7.
- At least one of R, R 1 , R 2 and R 3 is a pivalic acid residue.
- At least R and R 1 or R 2 and R 3 are simultaneously a pivalic acid residue.
- R, R 1 , R 2 and R 3 are simultaneously hydrogen.
- the compounds of formula (I) may be prepared as shown below in the experimental part.
- verbascoside may be reacted with an activated form of the selected carboxylic acid, such as a chloride or bromide of the acid, an anhydride or in the presence of condensing agents, according to the techniques typically used by an organic chemist.
- Verbascoside is commercially available and may be obtained by means of extraction from plants or plant cell cultures which contain it.
- verbascoside may be obtained from a selected cell culture of Syringa vulgaris, such as the cell line DSM 16857 deposited at DSMZ (Deutsche Sammlung Von Mikroorganismen und Zellkulturen, Braunschweig, Germany).
- the compounds of formula (I) have shown a platelet antiaggregant activity which, when the groups R, R 1 , R 2 and R 3 are not simultaneously hydrogen, according to an unconfirmed hypothesis, involves the in vivo release of verbascoside with delayed-release kinetics.
- the compounds of formula (I) where the groups R, R 1 , R 2 and R 3 are not simultaneously hydrogen have also shown a greater stability of verbascoside towards oxidation. Since an aqueous medium, such as a normal saline solution for example, is already capable of promoting the oxidation of verbascoside, such ester derivatives on the catecholic oxygens may be validly used in the place of verbascoside, especially when preparing pharmaceutical formulations in aqueous solution and in any case in normal saline medium, so as to allow the active ingredient to be released at the intestinal mucosa.
- an aqueous medium such as a normal saline solution for example
- sustained release kinetics of the compounds where the R, R 1 , R 2 and R 3 groups are not simultaneously hydrogen allows a once-a-day administration of the drug, with an obvious advantage for the patient.
- the preferred compounds of formula (I) are those where R and R 1 or R 2 and R 3 are simultaneously a carboxylic acid residue which may be hydrolyzed at a pH from 4.5 to 7. Especially preferred are the compounds of formula (I) where R and R 1 or R 2 and R 3 are simultaneously a pivaloyl group.
- compositions containing the compounds of formula (I) are a further object of the present invention.
- compositions of the invention can be prepared according to methodologies known to a person skilled in the art, such as those indicated in Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., N.Y., USA, 17th edition, 1985 .
- the compounds of formula (I) are contained in the compositions in weight percentages which may vary from 0.01%to 30%, preferably from 0.1% to 20%, more preferably from 1 %to 10%.
- Verbascoside (600 mg, 0.96 mmol) was dissolved in anhydrous DMF (6 mL) under hydrogen atmosphere. DIPEA (12 eq, 11.52 mmol, 2 mL) was added, followed by DMAP (4 eq, 500 mg).
- the reaction was left under stirring at 0°C for 30 min, then it was poured into a saturated aqueous solution of NH 4 Cl.
- the reaction mixture was then extracted twice with Et 2 O/EtOAc 1/1 and the organic phase was dried over sodium sulfate, filtered and evaporated thus obtaining 750 mg of raw compound (Ib).
- the raw fraction was purified by means of preparative HPLC obtaining 240 mg of pure product.
- a randomized, double-blind Phase II study was conducted to evaluate verbascoside activity in modulating the platelet aggregation (PA) values on subjects with at least one cardiovascular risk factor, selected from: age over 65 years, diabetes mellitus, hypertension, smoke, hyperlipidemia, waist circumference greater than 102 cm in men or 88 cm in women.
- cardiovascular risk factor selected from: age over 65 years, diabetes mellitus, hypertension, smoke, hyperlipidemia, waist circumference greater than 102 cm in men or 88 cm in women.
- cardiovascular risk factor selected from: age over 65 years, diabetes mellitus, hypertension, smoke, hyperlipidemia, waist circumference greater than 102 cm in men or 88 cm in women.
- cardiovascular risk factor selected from: age over 65 years, diabetes mellitus, hypertension, smoke, hyperlipidemia, waist circumference greater than 102 cm in men or 88 cm in women.
- platelet antiaggregants aspirin, clopidogrel, ticlopidine, prasugrel, ticagre
- exclusion criteria were: events of myocardial infarction, coronary revascularization (percutaneous or surgical), infarction, temporary ischemic attack, peripheral vascular pathology, and the consumption of corticosteroids and/or non-steroidal anti-inflammatory drugs in the last month.
- the experimentation was conducted on 100 subjects.
- the subjects were divided into three groups: one underwent a treatment with 50 mg/day of verbascoside (1 25-mg capsule twice a day); a second group underwent a treatment with 100 mg/day of verbascoside (2 25-mg capsules twice a day); the third group was treated with placebo (2 capsules twice a day).
- the treatment lasted 2 weeks.
- the subjects were randomly assigned to groups of four and divided into four categories: age over 60 years vs. age equal to or less than 60 years; male vs. female; current use of cigarettes yes vs. no; diabetes mellitus yes vs. no. These categories were generated because age, sex, smoking, and diabetes mellitus significantly influence PA.
- the blood samples were drawn from an antecubital vein on day 0 (before taking the drug) and at the end of the trial (week 2). The first 2-4 mL of blood were discarded to avoid the spontaneous activation of the platelets. All the subjects were sampled after at least 30 minutes of rest and 2 hours of fasting. Two 4.5 mL test tubes containing a 3.8% solution of sodium citrate were collected for each patient.
- PA was determined by means of light transmission aggregometry according to standard protocols.
- the blood was centrifuged (200 revs/10 min.) obtaining a platelet-rich-plasma (PRP).
- PRP platelet-rich-plasma
- PPP platelet-poor-plasma
- the platelets were stimulated with 1 ⁇ M of arachidonic acid (AA) and 5 ⁇ M of adenosine diphosphate (ADP).
- AA arachidonic acid
- ADP adenosine diphosphate
- the aggregation was measured at 37°C with a PACKS-4 aggregometer (Helena Laboratories). The curves were recorded for 6 min.
- the aggregation was measured at a maximum aggregation (maximum PA) and at 5 min (delayed PA).
- IPA platelet aggregation
- PD platelet disaggregation
- Verbascoside was obtained from a selected cell culture of Syringa vulgaris (cell line DSM 16857 deposited at DSMZ (Deutsche Sammlung Von Mikroorganismen und Zellkulturen, Braunschweig, Germany).
- Routine laboratory exams hematology, clinical chemistry, etc.
- measurements of vital functions were also conducted on the subjects at both time 0 and at the end of the treatment to evaluate the onset of side effects.
- the baseline PA values (PA at time 0) were assumed to be 50-60% with a standard deviation of 10-12%.
- the oxidation stability of the compounds of formula (I) was evaluated as a function of their antioxidant power, determined as the reactivity of the compound against the stable radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) in solution. High reactivity means poor stability under oxidizing conditions.
- DPPH 2,2-diphenyl-1-picrylhydrazyl
- the following final dilutions (from a solution in methanol having a double concentration) of the compound of formula (I) to be analyzed were prepared: 500 ⁇ g/mL, 100 ⁇ g/mL, 50 ⁇ g/mL, 10 ⁇ g/mL, 5 ⁇ g/mL, 2.5 ⁇ g/mL, 1 ⁇ g/mL, 0.5 ⁇ g/mL, 0.1 ⁇ g/mL, 0.05 ⁇ g/mL, 0 ⁇ g/mL.
- 500 ⁇ l of the compound to be tested at a certain concentration and 500 ⁇ l of DPPH were placed in a cuvette, they were all mixed and incubated in the dark at room temperature for 15 min.
- the solution was analyzed with a spectrophotometer at a wavelength of 515 nm (methanol as white).
- the color in the cuvettes varies from violet (DPPH without compound of formula (I)) to straw-yellow (DPPH with maximum inhibitory concentration of the compound of formula (I)).
- the percent inhibition of the radical reaction is defined as: Abs max DPPH alone ⁇ Abs DPPH + compound / Abs max ⁇ 100 .
- the antiradical activity is defined as the concentration of antioxidant substance which lowers the initial concentration of DPPH by 50%.
- Table I Compound Inhibitory activity (IC50) in ⁇ g/mL
- IC50 Compound Inhibitory activity in ⁇ g/mL
- the stability measurement was conducted by means of analytic HPLC techniques with a UV detector at 330 nm. The half-life is reported (in hours).
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Claims (10)
- Verbindungen der Formel (I):
wobei mindestens eines von R, R1, R2 und R3 ein Rückstand von Pivalinsäure ist. - Verbindungen der Formel (I) nach Anspruch 1, wobei die Estergruppen R-O-, R1-O-, R2-O- und R3-O- bis zu einem pH-Wert im Bereich zwischen 5 und 6,5, oder einem pH-Wert zwischen 6 und 7 oder einem pH-Wert zwischen 6,3 und 6,7 hydrolysierbar sind.
- Verbindungen der Formel (I) nach Anspruch 1 oder 2, wobei mindestens R und R1 oder R2 und R3 gleichzeitig ein Rückstand von Pivalinsäure sind.
- Verbindungen der Formel (I) nach Anspruch 3, wobei R und R1 ein Rückstand von Pivalinsäure sind und R2 und R3 H sind, oder R und R1 H sind und R2 und R3 ein Rückstand von Pivalinsäure sind.
- Pharmazeutische Formulierung, enthaltend mindestens eine Verbindung der Formel (I) nach einem der Ansprüche 1 bis 4 und pharmazeutisch verträgliche Hilfsstoffe.
- Verbindungen nach einem der Ansprüche 1 bis 4 oder Zusammensetzungen nach Anspruch 5 zur Verwendung als Thrombozyten-Antiaggregatoren.
- Verbindungen der Formel (I) zur Verwendung nach Anspruch 6, wobei die Estergruppen R-O-, R1-O-, R2-O- und R3-O- bis zu einem pH-Wert im Bereich zwischen 5 und 6,5, oder einem pH-Wert zwischen 6 und 7 oder einem pH-Wert zwischen 6,3 und 6,7 hydrolysierbar sind.
- Verbindungen der Formel (I) zur Verwendung nach Anspruch 6 oder 7 bei der Behandlung von Diabetespatienten.
- Verbindungen der Formel (I) zur Verwendung nach Anspruch 8 bei der Behandlung von Diabetespatienten, bei denen ein Risiko für Herz-Kreislauf-Erkrankungen besteht.
- Verbindungen der Formel (I) zur Verwendung nach Anspruch 8 oder 9 für eine einzelne tägliche Verabreichung.
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PCT/IB2016/051022 WO2016142797A1 (en) | 2015-03-06 | 2016-02-25 | Verbascoside derivatives |
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